Human CC motif receptor 7 (hereinafter referred to as “CCR7”) is a seven transmembrane-spanning domain G-protein coupled receptor (GPCR) that was originally found to be expressed in a lymphocyte-selective manner by EBV infection (Birkenbach et al., 1993, J. Virol. 67: 2209-2220). Later CCR7 was found to be a selective chemokine receptor for CCL19 and CCL21. Under physiological conditions, expression of CCR7 is restricted to naïve T and B lymphocytes and mature dendritic cells and plays a roles in regulating their migration, organization, and activation.
CCR7 activity has been implicated in a diverse variety of disease states, including chronic inflammatory conditions (Moschovakis et al., 2012, Eur J Immunol. 42:1949-55), atherosclerosis (Luchtefeld et al., 2010, Circulation 122:1621-28), HIV infection (Evans et al., 2012, Cytokine Growth Factor Rev. 23:151-57) and cancer (Ben-Baruch, 2009, Cell Adhesion Migration 3:328-33).
Various studies have revealed that CCR7 is expressed in a wide variety of tumour cells, including e.g. mantle cells lymphoma (MCL), follicular lymphoma, large B-cell lymphoma, AIDS-associated lymphoma, lymphoplasmacytic lymphoma, Burkitt lymphoma, B-cell acute lymphoblastic leukaemia, Hodgkin's disease, adult T-cell leukaemia/lymphoma, mycosis fungoides, blast crisis of chronic myeloproliferative syndromes, blast crisis of myelodysplastic syndromes, cancers such as breast cancer, non-small cell lung cancer, melanoma, gastric cancer or squamous cell carcinoma of the head and neck and colon carcinoma as B cell chronic lymphocytic leukemia, non-Hodgkin's lymphoma, breast cancer cell and malignant mammary tumor (WO 2007/003426). Further it is becoming clear that CCR7 plays a role in lymph node metastasis of various cancers (Viola and Luster, 2008, Annu Rev Pharmacol Toxicol. 48:171-97).
A reference mouse monoclonal antibody against human CCR7 (MAB197, Clone #150503) is commercially available from R&D Systems (www.RnDSystems.com).
WO 2007/003426 discloses the use of an antibody which binds to a CCR7 for treating cancer, whereby the tumor cells express CCR7. Binding of the antibody to the CCR7 expressing tumor cells is disclosed to inhibit migration of tumor cells and/or to kills tumor cells by one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and inducing apoptosis.
WO 2012/043533 discloses 8 different mouse monoclonal antibodies against human CCR7 that are useful for treating fibrosis or cancer. However, none of these antibodies has an IC50 of less than 7.4 nM for inhibiting intracellular Ca2+ signal transduction.
WO 2014/151834 discloses three different human anti-CCR7 antibodies generated in a Xenomous™ immunized with human CCR7-expressing cells, as well as a mouse anti-human CCR7 antibody and chimerization and humanization thereof. The human anti-CCR7 antibodies bind to different epitope on human CCR7 than the reference mouse monoclonal antibody MAB197. The antibodies are disclosed to be useful for treating inflammatory conditions, cancerous conditions, as well as conditions and complications arising from tissue or organ transplantation. WO 2014/151834 further discloses the isolation of mouse anti-human CCR7 antibodies, among which the blocking antibody MAb 22, which was chimerized by replacing its heavy chain constant regions with their human counterparts. This chimerized antibody retained its ability to bind human CCR7. The light chain of this chimerized antibody was further altered to generate a series MAb 22 variants with chimerized heavy chains and humanized light chains. WO 2014/151834 does not disclose which, if any, of these MAb 22 variants with humanized light chains has retained the ability to bind human CCR7.
There is however still a need in the art for further and improved anti-CCR7 antibodies that are useful in human therapy.